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Study Description

This is a Phase 2/3, open label, single arm study, evaluating how well hu14.18K322A works and how safe it is in combination with chemotherapy, in relapsed and refractory high-risk neuroblastoma (HRNB) patients.

The study is in 2 parts. The first part of the study will test two doses of hu14.18K322A to give with chemotherapy in 12 patients to confirm the best dose. Once the best dose is found, Part 2 of the study will recruit up to an additional 66 participants with relapsed disease and 66 participants with refractory disease.

Children and young people who take part in the study must be between 18 months and 18 years old at the time of consent and have confirmed HRNB that has spread to other parts of the body. It is expected that participants will receive up to 12 cycles of treatment. Once the treatment has finished, participants will be followed up to study long-term effects.

Inclusion Criteria

• Are ≥18 months to <18 years of age at time of informed consent or assent.
• Are initially diagnosed with histologically proven HRNB with metastatic disease.
• Have evaluable or measurable disease per International Neuroblastoma Response Criteria (INRC)
• Have a Lansky performance status of ≥50 (≤16 years ) or Karnofsky performance status ≥50% (for >16 years).
• Have recovered from the toxic effects of prior chemotherapies
• Are at least 2 weeks beyond any major tumor surgery
• Meet the following organ function criteria, as measured within 1 week prior to Investigational Medicinal Product (IMP) dosing:
  • BM function: i. Platelets ≥50 × 109/L ii. Absolute neutrophil count (ANC) ≥0.50 × 109/L
  • Renal function: i. Age-adjusted serum creatinine ≤1.5 × upper limit of normal (ULN) for age. ii. Estimated glomerular filtration rate (eGFR) at least 60 mL/min using the Schwartz formula.
  • Liver function: Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤3 × ULN and total bilirubin ≤1.5 × ULN.
  • Cardiac function: i. Shortening fraction ≥27% or ejection fraction of ≥50% on echocardiogram. ii. Corrected QT Interval on electrocardiogram (ECG) using the Fridericia formula (QTcF) ≤ 480 msec.
  • Lung function: i. Pulse oximetry considered normal in room air. No evidence of dyspnea at rest.
  • Central nervous system (CNS) function: i. Participants with a history of CNS disease must have no clinical or radiological evidence of active CNS disease at the time of study enrollment.
• If a fertile and sexually active woman of child-bearing potential (WOCBP), have a negative serum pregnancy test at Screening and then either a negative serum or urine test prior to each cycle and agree to use an acceptable and highly effective contraception method during the study and for at least 6 months after the last day of study treatment .
• If a fertile and sexually active male, agree to use condoms during the study and for at least 6 months after the last dose of study treatment
• If applicable based on age, are willing and able to provide voluntary written informed assent for participation in the study (as per local Institutional Review Board [IRB]/Independent Ethics Committee [IEC] requirements and if applicable based on regional age of consent) and to comply with all protocol requirements.
• Their parent or legal guardian (if applicable based on regional age of consent) is willing and able to provide voluntary written informed consent for the participant's involvement in the study.

Other inclusion or exclusion criteria may apply. 

Exclusion Criteria

• Any active uncontrolled infection at the time of enrollment. Any known history of infection with human immunodeficiency virus (HIV), or active or chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV).
• Any contraindications to any of the study treatments.
• Patients with >Grade 2 diarrhea.
• Patients with disease of any major organ system that would compromise their ability to withstand chemoimmunotherapy.
• Patients who have undergone a prior allogeneic stem cell transplant < 6 months ago or have undergone a solid organ transplant.
• Patients who are on hemodialysis.
• Patients who require or are likely to require pharmacologic doses of systemic corticosteroids while receiving treatment on this study except to manage allergic reactions
• Patients on any other immunosuppressive medications
• Patients who have received enzyme-inducing anticonvulsants including phenytoin, phenobarbital, or carbamazepine for at least 7 days prior to study enrollment.
• Patients who have been diagnosed with any malignancy other than neuroblastoma.
• Patients with symptoms of congestive heart failure.
• Patients with a history of Grade 4 allergic reactions to anti-GD2 antibodies or reactions that required permanent discontinuation of the anti-GD2 therapy.
• Patients participating in or planning to participate in another study that is either blinded or involves an IMP
• If female, are breastfeeding, pregnant, or planning to become pregnant, or, if sexually active and of child-bearing potential, are unwilling to use an effective birth control method until 6 months after the last dose of study medication
• Do not meet the following required washout periods prior to the administration of the first dose of hu14.18K322A:
  • 14 days from prior systemic myelosuppressive chemotherapy.
  • 7 days from prior systemic biologic antineoplastic agents (e.g. anti-cancer agents not known to be myelosuppressive - not associated with reduced platelet or ANC counts).
  • 14 days from systemic steroids.
  • ≥12 weeks from large field radiation therapy (i.e., total body irradiation, whole abdominal, total lung, ≥50% pelvis).
  • 6 weeks from prior craniospinal radiotherapy or Iodine-131-metaiodobenzylguanidine (131I-MIBG) therapy.
  • 2 weeks from radiotherapy to the primary tumor bed.
  • ≥7 days from small treatment field radiation.
  • 14 days or 5 half-lives (whichever is longer) from last administration of an IMP.
  • >7 days prior to study enrollment for drugs that are strong inducers or inhibitors of Cytochrome P450 3A4 (CYP3A4).
  • ≥21 days and with recovery of all associated toxicities from receiving cellular therapy (e.g., modified T lymphocyte cells, Natural Killer (NK) cells, dendritic cells).
• Ongoing need for any medication known or suspected to interfere with study treatment.

Other inclusion or exclusion criteria may apply. 

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Study Description

 This study is eligible for STEP-1 funding. Find more information here. 

Both Australia (Zero Childhood Cancer) and Canada (PROFYLE) have developed precision oncology programs for the pediatric population through which samples from childhood/adolescent cancers undergo in depth genetic profiling. OPTIMISE is a companion platform trial, which will link patients to novel targeted agents based on their tumor profile. The trial will have multiple basket arms based on the most common genetically altered pathways the investigators have identified in these childhood cancers. Each arm of the trial will be histopathology agnostic and test a rational, novel combination therapy, to maximise potential clinical benefit.

The information below is for Treatment Arm A which will be combining, for the first time, paxalisib with conventional chemotherapy in paediatric patients with high-risk malignancies.

Inclusion Criteria

• Patients must be diagnosed with a solid tumor, CNS tumor or lymphoma that has progressed despite standard therapy, or for which no effective standard therapy exists.
• Age <21 years at inclusion; patients 21 years and older may be included after approval by the Study Chair if they have a pediatric type recurrent/refractory malignancy.
• Patients must be enrolled on a precision medicine study (i.e. PROFYLE, ZERO or equivalent as agreed with Study Chair.
  • Tumour profiling should be performed as close to the time of study enrolment as possible; at a minimum profiling should have been performed on a sample obtained within 12 months prior to enrolment, or had confirmation that the targeted molecular aberration is still present from a tumour sample collected within the 12 months prior to enrolment. Patients for whom tumour profiling has been performed outside this window may only be enrolled after approval by the Study Chairs.
• Patients are eligible to enrol using existing sequencing results or other criteria such as immunohistochemistry (provided a report from a CLIA‐approved or equivalent laboratory is provided), but concurrent enrolment on a precision medicine study is still required.  
• Patients enrolled in a Phase I cohort must have either evaluable or measurable disease.
• Patients enrolled in a Phase II cohort must have measurable disease. Evaluable and measurable disease are defined by standard imaging criteria (RECIST V1.1, RAPNO or RANO) for the patient's tumor type.
• Disease evaluations, laboratory tests, and other clinical assessments that are considered standard of care may be undertaken at the patient's local oncology treatment centre with results transferred to study site for evaluation.
• Performance status: Karnofsky performance status (for patients > 16 years of age) or Lansky play score (for patients ≤ 16 years of age) ≥ 50%.
• Life expectancy ≥ 6 weeks.
• Patients must have fully recovered from the acute toxic effects of all prior anticancer therapy and must meet the following minimum duration from prior anticancer-directed therapy prior to enrolment.
• Adequate organ function.
  • Haematologic criteria:
    • Peripheral absolute neutrophil count (ANC) ≥1.0 x 109/L (unsupported) (i.e. at least 7 days post filgrastim; at least 14 days post PEG‐filgrastim (if administered)).
    • Platelet count ≥75 x 109/L (unsupported; defined as no platelet transfusions within prior 7 days).
    • Haemoglobin ≥80 g/L (transfusion is allowed).
  • Renal and hepatic function:
    • Serum creatinine ≤1.5 x upper limit of normal (ULN) for age
    • Total bilirubin ≤1.5 x ULN
    • Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤5 x ULN except in patients with documented tumour involvement of the liver who must have AST and ALT ≤10 x ULN
• Able to comply with scheduled follow-up and with management of toxicity.
• Females of childbearing potential must have a negative serum or urine pregnancy test.
• Fertile males must agree to use adequate contraception during the study and following completion of treatment.
• Provide a signed and dated informed consent form.

Additional Inclusion Criteria for Arm A

• For Cohort A1: Patients must have evaluable or measurable disease.
• For Cohort A2, Molecularly selected: Tumour must have a demonstrated pathogenic/likely pathogenic mutation in the PI3K/AKT/mTOR pathway from tumour DNA analysis, including:
  • Loss of function (LoF) in tumour suppressor genes or genes that normally act to downregulate the PI3K/AKT/mTOR pathway (PTEN, PIK3R1, TSC1, TSC2, DEPTOR)
    [Rationale: LoF variants involving these genes can lead to increased signalling of the PI3K/AKT/mTOR pathway. This includes single nucleotide variants (SNV), copy number 
    loss and structural variants (SV) leading to disruption of normal gene function.]
  • Gain of function (GoF) variants in oncogenes or genes that normally lead to upregulation of the PI3K/AKT/mTOR pathway.

• Cohort A3, Expanded drug-selection: Patients will be eligible if they have a demonstrated PI3K/AKT/mTOR pathway aberration in tumour from RNA expression analysis or proteomic analysis which would be predicted to benefit from PI3K/AKT/mTOR inhibition after discussion with the Arm A Study Chair, or demonstrated individual tumour sensitivity to a drug acting on this pathway through pre-clinical studies (in vitro and/or in vivo studies, which may include high-throughput drug screen and/or patient derived xenografts (PDX) and/or neurospheres). Patients with pathogenic/likely pathogenic mutation in relevant genes not meeting criteria for Cohort A2 will also be eligible.
• For Cohorts A2 and A3: Measurable disease as per RECIST, RAPNO or RECIL criteria. Patients with neuroblastoma will also be eligible if they have disease that is only evaluable by MIBG.
• For all Cohorts: Adequate cardiac function defined as
  • Shortening fraction of ≥27% by echocardiogram, or ejection fraction of ≥50% by gated 
    radionuclide study (MUGA); and
  • QTC <480 msec by the Fridericia formula.

Other inclusion or exclusion criteria may apply. 

Exclusion Criteria

• Patients with symptomatic CNS primary or metastatic tumors who are neurologically unstable or require increasing doses of corticosteroids or local CNS-directed therapy to control their CNS disease.
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter drug absorption of oral drugs.
• Clinically significant, uncontrolled heart disease (including history of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality), unstable ischemia, congestive heart failure within 12 months of screening.
• Known active viral hepatitis or human immunodeficiency virus (HIV) infection or any other uncontrolled infection.
• Presence of any ≥Grade 2 treatment-related toxicity with the exception of alopecia, ototoxicity, lymphopenia or clinically stable peripheral neuropathy
• Major surgery within 21 days of the first dose of investigational drug.
• Known hypersensitivity to any study drug or component of the formulation.
• Pregnant or nursing (lactating) females.
• Any other concomitant serious medical condition or organ dysfunction that in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the investigational drugs.

Additional Exclusion Criteria for Arm A:

Exclusion criteria for all Cohorts:

• Patients with significant uncontrolled hyperglycaemia that in the opinion of the investigator would compromise patient safety.
• Diabetic participants who require insulin therapy.
• Patients with active pneumonitis that is clinically symptomatic. 
• Patients with a history of myocardial infarction or coronary artery disease

Other inclusion or exclusion criteria may apply. 

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Study Description

This is a phase 1/2, open label, interventional clinical trial that will study the response rate of newly diagnosed pediatric low-grade glioma (PLGG) to oral administration of mirdametinib in combination with weekly vinblastine. Patients meeting all inclusion criteria for a given study group will receive mirdametinib twice daily (continuous) at a fixed dose (2 mg/m2 po BID up to 4 mg BID) for a total of 13 cycles (28 days cycle). Weekly intravenous vinblastine at MTD will be given for a total of 17 cycles.

The lead-in feasibility phase will be conducted to establish the maximum tolerated/recommended phase 2 dose (MTD/RP2D) of vinblastine in combination with mirdametinib combination using a modified Rolling-6 design. The established RP2D for mirdametinib (2 mg/m2 po BID up to 4 mg BID) will be used on this study. Mirdametinib will be administered on a continuous dosing schedule and de-escalated as necessary to an intermittent (3 weeks on, 1 week off) dosing schedule. Vinblastine will be escalated (or de-escalated) as necessary. Since these classes of agents do not have overlapping toxicities, the starting dose (i.e., Dose Level 0) for vinblastine is 4 mg/m2/week, which is 20% lower than the recommended single agent dose of vinblastine of 5 mg/m2/week. Dose Level 1 for vinblastine is 5 mg/m2/week and Dose Level -1 for vinblastine is 3 mg/m2/week.

Following the end of treatment, patients will be scheduled for a follow-up visit every 6 months for 36 months to evaluate PFS, TTP and OS. A total of 50 patients will be recruited as part of this clinical study.

Patients aged between 2 and 25 years old will be eligible, in order to include a maximum of patients affected by glioma. This study includes PLGG patients with neurofibromatosis type 1 (NF1) with a KIAA1549-BRAF fusion and patients with activation of the MAPK pathway with the exception of patients with a BRAFV600E mutation.

Response to treatment will be evaluated using the modified Response Assessment in Pediatric Neuro-Oncology (RAPNO), Response Assessment in Pediatric Neuro-Oncology (RANO) 1. Evaluation of quality of life will be measured using the Pediatric Quality of Life inventory (PedsQL) (Generic/Brain tumor modules).

This study will explore the genetic and epigenetic landscape of PLGG. Our biological study may include SNP array, nanoString studies, methylation array and RNAseq.

Inclusion Criteria

• Signed written informed consent prior to study participation.
• Study activities compliance: must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study, including disease assessment by contrast enhanced MRI.
• Aged ≥ 2 years to ≤ 25 years when starting mirdametinib.
• BSA ≥ 0.40m2
• Diagnosis:
  • Participants must have PLGG with NF1 gene mutation (based on clinical NIH criteria, germline NF1 mutation or molecular analysis of the tumor) or PLGG with KIAA1549-BRAF fusion (based on molecular analysis of the tumor) or PLGG with evidence of MAPK pathway alteration with the exception of patients with BRAF V600E mutation (based on molecular analysis of the tumor).
• Tumor tissue is required (at minimum, paraffin-embedded tissue block and additionally fresh frozen tissue [if available]). Patients with NF1 and Low Grade Glioma (LGG) can still be enrolled without tissue if no surgery or biopsy was conducted.
• Baseline MRI.
• Life expectancy greater than 6 months.
• Lansky/Karnofsky score ≥ 50.
• Normal organ and marrow function (see study protocol for specifics).
• Female and male patients of fertile age must agree to use highly effective contraceptive measures.
• Must be able to ingest by mouth and retain entirely the administered medication. Mirdametinib can not be administered via nasogastric tube or gastrostomy tube.

Other inclusion and exclusion criteria may apply and will be discussed with you by the study team. 

Exclusion Criteria

• Patients who are receiving other investigational agents.
• Cardiac: QTcB ≥ 480 msec or an absolute resting left ventricular ejection fraction (LVEF) of ≤ 49%.
• Patients who have any other malignancy, except if the other primary malignancy is neither currently clinically significant nor requiring active intervention.
• Tumor with BRAF V600E mutation.
• Patients who received previous systemic or radiotherapy treatment.
• Other severe and uncontrollable medical disease
• Blood pressure higher than 95th percentile for patient's age, height and gender.
• Increased risk of serious retinopathy and retinal vein occlusion.
• Known diagnosis of human immunodeficiency virus infection, hepatitis B or C.
• Previous major surgery within 2 weeks.
• History of allergic reactions to compounds of similar chemical or biological composition to mirdametinib.
• Pregnant or breastfeeding.

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Study Description

If you are a long-distance patient of >160 km, round trip - you may be eligible for STEP-1 travel funding. Find more information here. 

This is a pilot study to determine feasibility of adding intrathecal (IT) chemotherapy and maintenance therapy after high dose chemotherapy for treatment of newly diagnosed HR-EBTs in patients less than 6 years of age. Patients meeting all inclusion criteria will receive 3 cycles of multiagent chemotherapy induction (vinCRIStine, cyclophosphamide, CISplatin, etoposide) with IT cytarabine and hydrocortisone, and 3 cycles of consolidation with CARBOplatin, thiotepa, and autologous stem cell rescue (as per CCG 99703). Maintenance chemotherapy will then be given immediately after the completion of consolidation therapy and consist of risk-stratified oral chemotherapy using either "Maintenance A" (48 weeks) using tamoxifen and retinoic acid or "Maintenance B" (54 weeks) using metronomic isotretinoin, celecoxib, etoposide, temozolomide, and cyclophosphamide. Both arms of maintenance will receive monthly IT topotecan.

Following the end of treatment, patients will be scheduled for a follow-up visit every 3 months for 24 months to evaluate PFS and OS. Approximately 15 patients will be recruited as part of this clinical study.

Patients aged between 0 and 6 years old at the time of enrollment will be eligible. This study will only enrol patients with high risk Central Nervous System Embryonal Brain Tumors (CNS-EBTs) with histologic and/or molecular confirmation of diagnosis for ATRT intrinsic to the brain and spinal cord, group 3 and group 4 MB, pineoblastoma, CNS neuroblastoma, ETMR, including embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma and ETMR not otherwise specified), medulloepithelioma, CNS embryonal tumor with rhabdoid features (INI-1 intact) and CNS embryonal tumor, not otherwise specified.

Response to treatment will be evaluated using the modified RAPNO (Response Assessment in Pediatric Neuro-Oncology) 1.

This study will also explore the genetic landscape of CNS HR-EBTs. Our biological study will include genomic analyses of tumor and CSF with use of epigenomic analyses (methylation profiling) arrays, Nanostring sub-typing studies, Next generation sequencing analyses for DNA and/or RNA.

Inclusion Criteria

• Tumor Tissue Sample
• Age: Patient must be aged ≥ 0 years to ≤ 6 years at the time of definitive confirmation of histologic diagnosis of eligible CNS tumor.
• Diagnoses. Participants must have Central nervous system (CNS) HR-EBT including atypical teratoid rhabdoid tumour (ATRT), group 3 and group 4 medulloblastoma (MB), pineoblastoma, CNS neuroblastoma, embryonal tumor with multi-layered rosettes (ETMR including embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma and ETMR not otherwise specified), medulloepithelioma, CNS embryonal tumor with rhabdoid features (INI-1 intact) and CNS embryonal tumor, not otherwise specified. Metastatic disease included. Any extent of resection included.
• Cranial and Spine MRI. A baseline MRI brain and spine with and without contrast is required for all patients. cranial MRI (with and without gadolinium) must be done pre-operatively. Post-operatively, cranial MRI (with and without gadolinium) must be done.
• Lumbar Puncture (LP) CSF for cytopathology (strongly recommended but not mandatory; if medically feasible). A baseline LP CSF cytology either pre-operatively or post-operatively at least 10 days after definitive surgery for all patients if medically feasible (This is not mandatory and will not make the patient ineligible).
• Life expectancy: Patients must have a life expectancy of greater than 8 weeks from diagnosis.
• Performance level: Patients must have a performance status corresponding of a Lansky score ≥ 50.
• Organ Function Requirements: Participants must have normal organ and marrow function as defined below:
  • Adequate renal function defined as:
    • Creatinine clearance (12-24-hour urine collection) or radioisotope glomerular filtration rate (GFR) ≥ 60 ml/min/1.73m2
  • Adequate cardiac function defined as:
    • Shortening fraction of ≥ 27% by echocardiogram, or
    • Ejection fraction of ≥ 47% by radionuclide angiogram.
  • Adequate pulmonary function defined as:
    • No evidence of dyspnea at rest and a pulse oximetry > 94% on room air.
  • Adequate Bone Marrow Function defined as:
    • Peripheral absolute neutrophil count (ANC) > 1000/μL
    • Platelet Count > 100,000/μL (without transfusion for 3 days)
    • Hemoglobin greater than 8 gm/dL (may have received red blood cell (RBC) transfusions)
  • Adequate liver function defined as:
    • Total bilirubin ≤ 1.5X upper limit of normal (ULN) within normal institutional limits for age (patients with documented Gilbert's Disease may be enrolled with Study Chair approval and total bilirubin ≤ 2.0 × ULN)
    • Alanine Aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 100 U/L

Other inclusion and exclusion criteria may apply. 

Exclusion Criteria

• Patients who are receiving any other conventional anti-cancer agents or investigational agents.
• Patients who received previous therapy including radiotherapy or chemotherapy other than corticosteroids.
• Presence of another malignancy, except if the other primary malignancy is neither currently clinically significant nor requiring active intervention.
• Concomitant medications restrictions: Concurrent use of enzyme inducing anticonvulsants (e.g. phenytoin, phenobarbital, and carbamazepine), selected strong inhibitors of cytochrome P450 3A4 include azole antifungals, such as fluconazole, voriconazole, itraconazole, ketoconazole, and strong inducers include drugs such as rifampin, phenytoin, phenobarbitol, carbamazepine, and St. John's wort or CYP450 3A4 stimulators or inhibitors.
• Other uncontrollable medical disease: Patient has a severe and uncontrollable medical disease (i.e., uncontrolled diabetes, hyperglycemia, chronic renal disease or active uncontrolled infection), has chronic liver disease (i.e., chronic active hepatitis and cirrhosis), hypercholesterolemia (serum cholesterol >300 mg/dL), intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, active hyperparathyroidism, or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients who have a known diagnosis of human immunodeficiency virus (HIV) infection, hepatitis B or C.
• Ineligible diagnoses for study entry by neuropathology: This includes sonic hedgehog (SHH) and wingless (WNT) MBs, all ependymomas, all choroid plexus carcinomas, all high grade glial and glio-neuronal tumors, all diffuse midline gliomas, all primary CNS germ cell tumors, all primary CNS sarcomas, all primary or metastatic CNS lymphomas and solid leukemic lesions (chloromas, granulocytic sarcomas).
• The participant or parent(s)/guardian(s) cannot comply with the study visit schedule and other protocol requirements, in the investigator's opinion.

Other inclusion and exclusion criteria may apply. 

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Study Description

The main goal of this study is to test a new medicine, Risvutatug Rezetecan also called Ris-Rez. We want to see if this medicine can help people with certain types of cancer, whether its safe to use, how well people tolerate it, and how their bodies handle the drug (how its absorbed and broken down). This research is for adolescents and adults who have either: Osteosarcoma, which is a type of bone cancer, or Soft Tissue Sarcoma, which is a type of cancer that starts in soft body tissues (like muscle, fat, or nerves). In both cancer types the cancer must have already been treated, but has come back or spread, and cant be removed by surgery

Inclusion Criteria

• Participants must be ≥ 12 years of age.
• Has histologically confirmed unresectable advanced or metastatic R/R OSA (Cohort 1) or unresectable advanced or metastatic STS (Cohort 2) that has progressed to at least one prior line of systemic therapy.
• Has documented disease progression on the last line of systemic treatment as confirmed by radiological imaging
• Has an ECOG performance status of 0 or 1, or Lansky PS/Karnofsky PS ≥ 70% for adolescent participants, with no deterioration in the 2 weeks prior to first dose/randomization.
• Has adequate organ function.
• All participants, or their legal guardians, must provide signed informed consent and agree to follow the study protocol before starting any study activities

Exclusion Criteria

• Has received any prior therapy with an antibody-drug-conjugate (ADC) with a TOPO1-inhibitor payload.
• Has known sensitivity to study intervention components or excipients or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.
• Has severe, uncontrolled or active cardiovascular disorders.
• Known active infectious diseases requiring systemic treatment or known Human immunodeficiency virus (HIV).
• Has symptomatic brain metastases or untreated progression exclusively due to brain metastasis during or after the last treatment prior to screening, evidence of leptomeningeal/meningeal/brainstem metastasis or evidence of spinal cord metastases.
• Has received treatment with an investigational agent within 4 weeks of the first dose of study intervention.
• Is pregnant or breastfeeding.

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Study Description

 This study is eligible for STEP-1 funding. Find more information here. 

Patients will be enrolled on either Cohort A for newly diagnosed DIPG or on Cohort B for those with progressive / refractory DIPG or progressive / recurrent / refractory H3K27-altered HGG. Each cohort will receive ACT001 at 875 mg/m2 orally BID for 28 days (1 cycle of treatment), up to a maximum dose of 1700 mg BID. If patients are experiencing clinical benefit from study therapy, they will continue to receive ACT001 in repeat 28-day cycles for up to 26 cycles (approximately 2 years) or until disease progression, whichever occurs first. Continuation of treatment beyond 26 cycles may be considered if patients are receiving clinical benefit from the study, at the discretion of the sponsor and treating physician.

Inclusion Criteria

• Patients must be ≥ 12 months and ≤ 39 years of age at the time of study enrollment.
• Diagnosis:
  • Cohort A: Newly Diagnosed DIPG
    • Patients with newly-diagnosed DIPG with typical MRI findings (tumors with a pontine epicenter and diffuse involvement of at least 2/3 of the pons) with or without biopsy and have completed radiation therapy (RT) within 28 to 35 calendar day prior to start of therapy.
    • Patients must have started RT <42 calendar days of radiographic diagnosis (for non-biopsied DIPG patients only) or definitive surgery, whichever is later. It is strongly recommended patients begin RT within 31 days of diagnosis/definitive surgery.
      • If a biopsy was performed, the date of surgical biopsy will be considered the date of definitive diagnostic surgery; if a patient underwent two upfront surgeries [e.g., biopsy then debulking], this is the date of the second surgery)
    • Patients must have received RT, but no other anti-cancer therapy other than surgery, and/or steroids prior to enrollment.
  • Cohort B: progressive/refractory/recurrent DIPG or H3K27-altered HGG
    • Patients with DIPG (no biopsy required) or pathologically-confirmed (at diagnosis or recurrence) extra-pontine H3K27-altered HGG who have progressive, refractory or recurrent disease following frontline treatment that included at least focal RT. Patients with refractory disease must have completed RT >6 months prior to study enrollment.
    • Patients with progressive disease only at the primary site(s) must have completed RT more than 3 months prior to enrollment.
    • Patients with progressive disease only at the primary site(s) who completed radiation therapy 3 to 6 months prior to enrollment must have had at least one follow up MRI to confirm progression (rather than pseudo- progression)
    • Patients with progressive disease due to the development a new metastatic site are eligible as long as eligibility criteria 3 (disease status) and 5 (prior RT) are met.
    • Patients with metastatic disease are eligible.
• Disease Status
  • Cohort A: patients may have any disease status but must have completed initial radiation therapy (RT) before enrollment.
  • Cohort B: Patients must have measurable disease assessable by MRI imaging. Patients may have metastatic disease. Lesions irradiated within the last 6 months are not considered measurable unless they show definitive progression following RT.
• Performance Level: Karnofsky Performance Scale score ≥ 50% for patients > 16 years of age and Lansky Performance Scale score > 50% for patients ≤ 16 years of age (applies to all patients) Note: Patients who are unable to walk because of paralysis, but who are capable of using a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Prior anti-cancer therapy:
  • For Cohort A ONLY:
    • Patients must not have received any prior therapy other than surgery, radiation (focal to disease) and/or steroids (dexamethasone with goal to wean dexamethasone throughout protocol therapy).
    • Patients must enroll and start treatment on study between 28 and 35 calendar days post-completion of RT.
    • Patients must have started RT <42 calendar days of initial diagnosis (defined as the date of diagnostic biopsy or resection; if a patient underwent two upfront surgeries [e.g., biopsy then resection or debulking], this is the date of the second surgery).
    • Radiotherapy must have been administered at standard dose of 54 Gy for DIPG patients. Any variances in the radiotherapy dose within 10% of the standard doses outlined above will be discussed with the Study Chair (or their delegate) to confirm eligibility prior to study enrollment.
  • For Cohort B ONLY: Patients must have fully recovered from adverse events due to prior treatment with investigational or conventional agents must have recovered to a severity of Grade 0 or Grade 1 (per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 or higher), with the exception of alopecia.
    • Notes to the above for Cohort B: Patients with chronic Grade 2 toxicities may be eligible per discretion of the Investigator and Sponsor (e.g., Grade 2 chemotherapy-induced neuropathy). Grade 2 or 3 toxicities from prior anti-tumor therapy that are considered irreversible - defined as having been present and stable for > 6 months (such as ifosfamide-related proteinuria) may be allowed if they are not otherwise described in the exclusion criteria AND there is agreement to allow by both the Investigator and Sponsor.)
• The wash out period between the prior anti-cancer chemotherapy, and first dose of ACT001 (cycle 1 day 1) must be:
  • Myelosuppressive chemotherapy: At least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea).
  • Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth factor.
  • Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair.
  • Immunotherapy: At least 42 days after the completion of any type of immunotherapy, e.g. tumor vaccines.
  • Monoclonal antibodies: > 21 days must have elapsed from the infusion of last dose of antibody and toxicity related to antibody therapy must be recovered to Grade ≤ 1
  • Radiation therapy:
    • For Cohort B, patients with refractory disease must have received their last fraction of frontline craniospinal or focal RT > 6 months prior to study enrollment. Patients that have received re-irradiation for progression must have received their last fraction of focal radiation >6 weeks or craniospinal radiation >6 weeks prior to study enrollment.
  • Stem Cell Transplant: Patients must be ≥ 3 months since autologous stem cell transplant. Patients who received allogenic stem cell transplant or solid organ transplant are not eligible for study
• Organ Function Requirements (applies to all patients)
  • Adequate bone marrow function defined as:
    • Peripheral absolute neutrophil count (ANC) > 1000/mm³
    • Platelet count > 100,000/mm³ (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
  • Adequate renal function defined as:
    • Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m² or
    • A serum creatinine based on age/gender as follows (Schwartz et al. J. Peds, 106:522, 1985): Age Maximum Serum Creatinine (mg/dL) Male Female 1 to < 2 years 0.6 0.6 2 to < 6 years 0.8 0.8 6 to < 10 years 1.0 1.0 10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.4 ≥ 16 years 1.7 1.4
    • Adequate liver function defined as:
      • total bilirubin within normal institutional limits
      • AST (serum glutamic-oxaloacetic transaminase [SGOT]) / ALT (serum glutamic-oxaloacetic transaminase [SGPT]) ≤ 2.5 × institutional upper limit of normal
      • Serum albumin ≥ 2 g/dL
  • Adequate cardiac function defined as
    • Ejection fraction of ≥ 50% by echocardiogram
    • QTc ≤ 480 msec (by Bazett formula)
  • For Cohort B: Adequate neurologic function defined as:
    • Patients with seizure disorders may be enrolled if seizures are well- controlled. Well controlled is defined by no increase in seizure frequency in the 7 days prior to enrollment.
    • Patients with neurological deficits should have deficits that are stable for at least the 7 days prior to enrollment.
• Informed Consent: All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
• Absence of other clinically significant concomitant active medical disorder, based on the investigator's judgement.

Other inclusion and exclusion may apply and will be discussed with you by the study team. 

Exclusion Criteria

• Cohort A only: Patients with metastatic disease.
• Concomitant medications:
  • Corticosteroids:
    • Cohort A - Patients receiving corticosteroids are eligible regardless of dosing
    • Cohort B - Patients receiving corticosteroids who have been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are eligible
  • Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are not eligible (Refer study inclusion criteria relating to anti-cancer therapies)
    • Cohort A - Patients that have received any anti-cancer treatment other than RT are not eligible.
  • Investigational Drugs: Patients who are currently receiving another investigational drug are not eligible.
  • Anticonvulsants should be used as clinically indicated. The use of enzyme inducing anticonvulsants is not permitted
  • LHRH agonist / antagonists are not permitted
  • High Dose Biotin (B7) supplements are not permitted
• Concomitant medications used with caution: selective serotonin reuptake inhibitor (SSRI) such as Lexapro, Fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft), citalopram (Celexa), and escitalopram should be used with caution.
• Infection: Patients who currently have an uncontrolled infection (in the opinion of the PI) are not eligible.
• Patients who have received a prior solid organ transplantation are not eligible.
• Pregnant or breast-feeding women will not be entered on this study due to unknown risks of fetal and teratogenic adverse events as seen in animal/human studies. Pregnancy tests must be obtained in girls who are postmenarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.
• Patients of childbearing or child fathering potential must agree to use adequate contraceptive methods (hormonal or barrier method of birth control; abstinence) while being treated on this study and for 3 months after completing therapy. Note: The definition of effective contraception will be based on the judgement of the principal investigator or a designated associate.
• Patients who are in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.
• Patients who have previously received either ACT001 or parthenolide are not eligible.

Other inclusion and exclusion may apply and will be discussed with you by the study team. 

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Study Description

Substudy 01A is part of a platform study. The purpose of this study is to assess the efficacy and safety of zilovertamab vedotin in pediatric participants with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), diffuse large B-cell lymphoma (DLBCL)/Burkitt lymphoma, or neuroblastoma and in pediatric and young adult participants with Ewing sarcoma.

Inclusion Criteria

• For hematological malignancies: Confirmed diagnosis of B-precursor B-ALL or DLBCL/Burkitt lymphoma according to World Health Organization (WHO) classification of neoplasms of the lymphoid tissues.
• For solid tumor malignancies: Histologically confirmed diagnosis of neuroblastoma or Ewing sarcoma.

Exclusion Criteria

• History of solid organ transplant.
• Clinically significant (ie, active) cardiovascular disease.
• Known history of liver cirrhosis.
• Ongoing Grade >1 peripheral neuropathy.
• Demyelinating form of Charcot-Marie-Tooth disease.
• Diagnosed with Down syndrome.
• Ongoing graft-versus-host disease (GVHD) of any grade or receiving systemic GVHD treatment or prophylaxis.
• History of human immunodeficiency virus (HIV) infection.
• Contraindication or hypersensitivity to any of the study intervention components.
• Received prior radiotherapy within 4 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities.
• Ongoing, chronic corticosteroid therapy (exceeding 10 mg daily of prednisone equivalent). Prednisone equivalent dosing must have been stable for at least 4 weeks before Cycle 1 Day 1 (C1D1).
• Received a strong cytochrome P450 3A4 (CYP3A4) inhibitor within 7 days or a strong CYP3A4 inducer within 14 days before the start of study intervention or expected requirement for chronic use of a strong CYP3A4 inhibitor or inducer during the study intervention period and for 30 days after the last dose of study intervention
• Received prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study intervention (except for prophylactic intrathecal chemotherapy and/or cytoreductive therapy with steroids/hydroxyurea.
• Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.
• Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
• Known additional malignancy that is progressing or has required active treatment within the past 1 year.
• Active infection requiring systemic therapy.
• Known history of Hepatitis B or known active Hepatitis C virus infection.
• Participants who have not adequately recovered from major surgery or have ongoing surgical complications.

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Study Description

Brief Summary:

The study evaluates CLR 131 in children, adolescents, and young adults with relapsed or refractory High Grade Glioma (HGG) for which there are no standard treatment options with curative potential.

Part A for Solid Tumors, Lymphoma, and Malignant  Brain Tumors is now closed. This study is exclusively enrolling on Part B for HGG

Detailed Description:

Even with standard, highly toxic multimodality therapies and salvage regimen, most pediatric patients with primary metastatic or relapsed solid tumors are confronted with a poor prognosis. For these patients there is currently no accepted successful treatment regimen. There is a need for new drugs, including targeted radiopharmaceuticals, preferably with cancer-specific uptake and broad applicability for these rare pediatric malignancies.

CLR 131 is a radioiodinated therapeutic that exploits the selective uptake and retention of phospholipid ethers (PLEs) by malignant cells. Cellectar Biosciences' novel cancer-targeted small-molecule compound (CLR1404) is radiolabeled with the isotope iodine-131 (I-131). CLR 131 has demonstrated tumor selective uptake across numerous adult and pediatric cancer cell types. Therapeutic efficacy has been demonstrated in various pediatric and adult-type cancer xenograft models, confirming the ability of CLR 131 to target tumors.

Based on the critical unmet medical need for effective agents with novel mechanisms of action in relapsed pediatric cancers and initial preclinical and clinical experience with radioiodinated CLR1404, Cellectar Biosciences has chosen to assess CLR 131 in a phase 1 pediatric trial.

Inclusion Criteria

• Previously confirmed (histologically or cytologically) HGG that is clinically or radiographically suspected to be relapsed, refractory, or recurrent. Patients with DIPG are exempt from histologic verification if they have typical MRI findings of DIPG (i.e., hypo- or isointense on T1-weighted imaging, hyperintense on FLAIR or T2-weighted imaging, epicenter in the pons, greater than 50% of pons involved) and the risk of tumor biopsy is prohibitive. Patients with a diagnosis of ependymoma may enroll with prior Sponsor approval.
  • Refractory is defined as:
    • Lack of response (stable disease) or disease progression while on therapy
    • Disease progression within 3 months of cessation of therapy
• Patient is ≥ 10 years and ≤ 25 years of age at time of consent/assent
• Patients ≥ age 16 years must have a Karnofsky performance status of ≥ 60. Patients < age 16 years must have a Lansky performance status of ≥ 60
• Patients must meet the following lab criteria:
  • Platelets ≥ 75,000/µL [75 x 10⁹ /L] (last transfusion, if any, must be at least 1 week prior to study registration, and, unless deemed medically necessary, no transfusions are allowed between registration and dosing)
  • Absolute neutrophil count ≥ 750/µL [0.75 x10⁹/L]
  • Hemoglobin ≥ 8 g/dL [80 g/L] (last transfusion must be at least 1 week prior to study registration, and, unless deemed medically necessary, no transfusions are allowed between registration and dosing)
  • Using the bedside Schwartz formula [Schwartz 2009], estimated GFR (creatinine clearance) > 60 ml/min/1.73m²
  • Alanine aminotransferase < 3 × ULN
  • Bilirubin < 2 × ULN
• At least 1 measurable intracranial lesion with longest diameter of at least 10 mm on any imaging sequence.
• Patients with previously known neurological deficits must be clinically stable for one week prior to enrollment and be able to complete all study related procedures
• If patient receives steroids for neurological symptom control, the dose must be stable (unchanged for one week prior to enrollment) or on a steroid tapering regimen. Initiation of steroids per routine care immediately prior to CLR 131 dosing is acceptable.
• Patient or his or her legal representative is judged by the Investigator to have the initiative and means to be compliant with the protocol.
• Patient or his or her legal representative has the ability to read, understand, and provide written informed consent for the initiation of any study-related procedures.
• Female patients of childbearing potential must have a negative pregnancy test at screening and within 24 hours of dosing. It is recommended that female caregivers of childbearing potential have a negative pregnancy test within one week of dosing.
• Patients of childbearing potential must practice an effective method of birth control while participating on this study to avoid possible harm to the fetus.

Exclusion Criteria

• Antitumor therapy or investigational therapy, within three-half-lives of the agent preceding the present study. For certain types of radiation (craniospinal, total abdominal, whole lung [spot irradiation to skull-based metastases is not considered craniospinal radiation for the purposes of this study]), at least 3 months must have elapsed. Palliative focal radiation to non-target lesions should be completed at least 2 weeks prior to dosing. NOTE: Patients participating in non-interventional clinical trials (i.e., non-drug) are allowed to participate in this trial.
• History of hypersensitivity to thyroid protection medication (e.g., potassium iodide, Lugol’s solution, etc.)
• Any other concomitant serious illness or organ system dysfunction (including cardiac and pulmonary dysfunction) that in the opinion of the Investigator would either compromise patient safety or interfere with the evaluation of the safety of the test drug.
• Major surgery within 6 weeks of enrollment unless delay in therapy poses unacceptable risk to the patient due to clinical progression (enrollment of such patients should be discussed with Medical Monitor).
• Known history of human immunodeficiency virus or uncontrolled, serious, active infection.
• Pregnancy or breastfeeding